The lipodystrophy syndrome is a newly recognized syndrome among HIV-infected men and women. The investigator has shown in a recent collaboration with the Framingham Heart Study that patients with lipodystrophy demonstrate a significant insulin resistance syndrome , characterized by hyperinsulinemia, dyslipidemia and increased diastolic blood pressure. Insulin resistance associated with the HIV lipodystrophy syndrome poses a considerable risk for long-term increased cardiovascular disease, but little is known of its mechanism nor has treatment been established. Fat redistribution is strikingly abnormal in affected female patients, but the gender-specific cardiovascular consequences of the insulin resistant phenotype are not known. In this grant proposal this project will determine the gender-specific characteristics of the insulin resistant phenotype in HIV-infected men and women. The investigator will test the hypothesis that truncal fat gain and subcutaneous fat loss contribute independently to the insulin resistant phenotype, and furthermore, that hyperinsulinemia impairs fibrinolysis and disrupts endothelial function leading to increased carotid intimal medial thickness and stenosis. The investigator will test the hypothesis that increased circulating free fatty acids (FFA) resulting from fat redistribution contribute to insulin resistance and increased endogenous hepatic glucose production. Simultaneously, a novel approach to the treatment of insulin resistance in patients with the lipodystrophy syndrome, in which there was shown an effect of metformin to lower insulin levels in preliminary studies. In the final aim of the proposal, the project will investigate in vitro, the independent and combined effects of PI's and nucleoside analogues on human subcutaneous and visceral adipocytes. These studies will allow us to determine for the first time the depot-specific mechanisms by which these agents may lead to subcutaneous fat loss and visceral fat gain and thereby promote insulin resistance. This project will study the effects of these agent on adipogensis, differentiation, insulin sensitivity and expression of PPAR and other adipocyte regulatory genes using thiazolidinediones to determine whether PPAR gamma activation can rescue the differentiated phenotype. The novel studies in this grant proposal will provide important new information on mechanisms, cardiovascular effects and optimal treatments for insulin resistance in the HIV-lipodystrophy syndrome. The proposed studies represent a significant collaborative effort between clinical researchers, adipocyte biologists, epidemiologists and nutritional biochemists in satisfaction of the mandate of the RFA.